DESCRIPTION: (Verbatim from applicant?s abstract): Impairment of learning and memory is a common phenomenon associated with advancing age, although the underlying mechanisms are not clearly understood. Based on previous reports of age-correlated increases in dynorphin expression in the brain and on studies of effects of dynorphin in vivo and in vitro, we are investigating a possible role of the endogenous opioid neuropeptide dynorphin in age-associated decline in mental health. We have recently found that moderately aged prodynorphin knockout mice perform significantly better than similarly aged wild-type mice in a spatial learning and memory task, suggesting an important role of this peptide in causing memory dysfunction. We hypothesize that age-related alterations in hippocampal dynorphin levels contribute substantially to functional impairment of learning and memory by altering glutamate neurotransmission or other synaptic activities. To test this hypothesis, we propose a set of behavioral assays to assess hippocampal-dependent learning and memory processes in dynorphin knockout mice and wild-type mice of varying ages. In addition, we will supplement the behavioral studies with electrophysiological analysis and anatomical characterization of specific sites within hippocampus where dynorphin is localized. These experiments will allow us to determine the functional role of hippocampal dynorphin in modulating neuronal activity associated with learning and memory processes, which may lead to novel therapeutic strategies for the treatment of learning and memory dysfunction.